The primary objectives of this proposal examine immunologic mechanisms of anti-HER2 therapies. The general hypothesis is that trastuzumab, when combined with chemotherapy, actively immunizes patients leading to the generation of adaptive immune effector cells or antibodies that are associated with therapeutic efficacy. Immune effectors generated at tumor sites and regional lymph nodes and released into blood may be potential biomarkers of trastuzumab response. Trastuzumab has in part an immunologic mechanism of action, and preliminary results from Dr. Knutson and Dr Clynes suggest that an adaptive immune response is responsible for the clinical actions of trastuzumab. An advantage of immune biomarkers is that a simple blood draw may suffice for detection. Our specific aims include: 1) To determine whether anti-HER2 antibody responses, generated during chemotherapy and trastuzumab in breast cancer patients, are associated with clinical responses. We will perform retrospective analyses of endogenous HER2-specific antibody responses using serum samples collected from metastatic breast cancer patients treated with chemotherapy and trastuzumab; 2) To determine whether a HER2-specific T cell immune response is induced in HER2+ breast cancer patients treated with chemotherapy and trastuzumab. We will perform a prospective study evaluating T cell and antibody immunity in adjuvant and metastatic breast cancer patients treated with chemotherapy and trastuzumab; 3) To determine whether the improved disease-free survival and overall survival in patients treated in the adjuvant setting with combination of chemotherapy and trastuzumab is associated with the Fc? receptor genotype of the patient. PUBLIC HEALTH RELEVANCE: HER2-positive breast cancers are very aggressive and account for 15-20% of all breast cancer cases. Trastuzumab, an antibody against the HER2 protein, has revolutionized the treatment for these cancers, but not all HER2-positive patients respond to trastuzumab and therefore, additional tissue and blood tests that can better predict the response to trastuzumab are needed to more effectively personalize therapy. We propose to evaluate blood immune cells as indicators of trastuzumab response that may help identify those patients most likely to benefit from trastuzumab.